U.S. patent number 10,285,938 [Application Number 15/632,350] was granted by the patent office on 2019-05-14 for composition for the treatment of burns, diabetic wounds, other types of wounds and subsequently greatly reduced scarring.
This patent grant is currently assigned to ISSAR Pharmaceutical. The grantee listed for this patent is Ram Isanaka, Jesse Jaynes. Invention is credited to Ram Isanaka, Jesse Jaynes.
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United States Patent |
10,285,938 |
Isanaka , et al. |
May 14, 2019 |
Composition for the treatment of burns, diabetic wounds, other
types of wounds and subsequently greatly reduced scarring
Abstract
Antimicrobial peptides represent a relatively new discovery in
the immune system pathway. Recent designs of synthetically
engineered antimicrobial peptides have demonstrated increased
potency and efficacy/tolerability, enhanced specificity, and
reduced toxicity in comparison. One such peptide, XYLENTRA.RTM.,
has shown/demonstrated significant promise from significant in
vitro studies against a large + pathogens. Additionally, extensive
animal studies have shown that the XYLENTRA.RTM. is an
antimicrobial peptide against a large number of pathogens. The
XYLENTRA.RTM. peptide is also solute resistant. The peptide
XYLENTRA.RTM. has shown/demonstrated significant antibacterial
activity on test organisms Staphylococcus aureus MTCC 96 and
Pseudomonas aeruginosa. MTCC741. A substantial decrease in the
microbial population level was observed in animals treated with
peptide using the protocol described in detail in the
application.
Inventors: |
Isanaka; Ram (Warren, NJ),
Jaynes; Jesse (Auburn, AL) |
Applicant: |
Name |
City |
State |
Country |
Type |
Isanaka; Ram
Jaynes; Jesse |
Warren
Auburn |
NJ
AL |
US
US |
|
|
Assignee: |
ISSAR Pharmaceutical
(IN)
|
Family
ID: |
57994312 |
Appl.
No.: |
15/632,350 |
Filed: |
June 25, 2017 |
Prior Publication Data
|
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|
|
Document
Identifier |
Publication Date |
|
US 20170290770 A1 |
Oct 12, 2017 |
|
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
|
14756169 |
Aug 11, 2015 |
9737584 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K
47/183 (20130101); A61K 9/0014 (20130101); A61K
47/10 (20130101); A61K 47/06 (20130101); A61K
47/12 (20130101); A61K 38/08 (20130101); A61K
47/24 (20130101); A61K 9/06 (20130101); A61K
38/00 (20130101); A61K 47/14 (20130101); A61K
47/02 (20130101) |
Current International
Class: |
A61K
38/08 (20190101); A61K 47/12 (20060101); A61K
47/14 (20170101); A61K 47/24 (20060101); A61K
9/06 (20060101); A61Q 19/00 (20060101); C07K
14/00 (20060101); A61K 47/18 (20170101); A61K
9/00 (20060101); A61K 47/02 (20060101); A61K
47/06 (20060101); A61K 47/10 (20170101); A61K
38/00 (20060101) |
Field of
Search: |
;514/1.1,21.4
;530/326,300 ;424/93.4 |
References Cited
[Referenced By]
U.S. Patent Documents
Primary Examiner: Ha; Julie
Attorney, Agent or Firm: Dodds; John Zapatero; Carlos
Parent Case Text
REFERENCE TO CROSS-RELATED APPLICATIONS:
This application is a divisional of application Ser. No.
14/756,169, filed on Aug. 11, 2015, granted as U.S. Pat. No.
9,737,584, and claims priority date of Provisional Application No.
62/070,481 filed on Aug. 26, 2014.
Claims
The invention claimed is:
1. A method of treating a wound, which comprises: administering to
the wound a therapeutically effective dose of a composition
comprising an antimicrobial peptide, wherein the antimicrobial
peptide comprises SEQ ID NO:1, thereby yielding significant
reduction in scarring caused from wounds.
2. The method of claim 1, wherein the wound is a burn.
3. The method of claim 1, wherein the wound is a diabetic
wound.
4. The method of claim 1, wherein the antimicrobial peptide
exhibits antimicrobial activity on Staphylococcus aureus and
Pseudomonas aeruginosa.
5. The method of claim 1, wherein the composition is in the form of
a cream.
Description
SEQUENCE LISTING
The instant application contains a Sequence Listing which has been
filed electronically in ASCII format and is hereby incorporated by
reference in its entirety. Said ASCII copy, created on Aug. 6,
2018, is named ISSAR_DIVISIONAL_SL.txt and is 751 bytes in
size.
FIELD OF THE INVENTION
This invention relates to a novel composition of cream that can be
used with proprietary synthetically designed bioactive peptides for
the treatment of wounds. This augmented cream can be used to
specifically treat burns and chronic wounds such as those found in
diabetic wounds and eroded or cracked tissue particularly on the
extremities. It is shown to significantly accelerate healing and
protect patients from infection. Treatment of wounds with the cream
also greatly reduces scarring.
BACKGROUND OF THE INVENTION
Burn Wounds
Over 1.5 million people suffer burns each year in the United
States. More than 5,000 of these people will die as a direct result
of the significant loss of the skin's integrity and subsequent
bacterial invasion into the unprotected internal milieu of their
bodies. Sepsis accounts for greater than 50% of the deaths related
to patients who suffer from burns. Transmission of multi-resistant
organisms to other patients, particularly in contained burn units,
not only increases morbidity, but also adds an enormous cost to the
healthcare system.
The current treatment of the burned patient involves fluid
resuscitation, hemodynamic stabilization and the application of
topical antimicrobials prior to wound excision and grafting.
Bacteria flourish in dead tissue and intravenous antibiotics cannot
penetrate this tissue because of its impaired blood supply. This
necessitates the use of topical antimicrobials that are meant to
curtail the systemic invasion of bacteria. Unfortunately, the
commonly employed topical antimicrobials are often not enough to
prevent the fatal consequences of burn wound sepsis. Synthetic
antimicrobial peptides are specific proteins designed to encompass
a greater spectrum of activity against bacteria (including
multi-drug resistant organisms) and fungus than traditional topical
agents.
Our proprietary peptide designs are extremely stable in hostile,
non-physiologic environments. Alterations in the wound milieu,
characteristics of burns, do not affect the potency or properties
of the peptide making the designed peptides more effective and
valuable to practitioners who manage burns, and infected or
adversely colonized wounds. Sufficient promise was shown by several
peptides through in vitro and in animal studies, to lead to the
selection of one to be tested in several human clinical trials.
An initial double blind randomized, phase II/III clinical trial for
the evaluation of a cream based peptide preparation in the topical
treatment of burn wounds was conducted at Gandhi Medical College
Hospital in Hyderabad, India in 2008. The mean duration to reach
the total wound closure for peptide treated patients was found to
be 8.4 days while the placebo group was 11.1 days. This was
statistically significant at the (P<0.001). A second study
consisting of 120 burn patients, begun in late 2008 was carried out
at two hospitals in Hyderabad, India. In these studies the patients
received no additional antibiotic therapy and none of the wounds
were debrided. The final report indicated that there were no
infections and significant accelerated healing with minimal
scarring and the patients had significantly fewer hospital
visits.
A final phase III study was recently completed utilizing a new
cream composition combined with a very effective designed
antimicrobial peptide. The results of this trial are found in this
application.
Chronic Wounds
The loss of the skin's protective barrier as the result of unhealed
wounds fosters the susceptibility to bacterial infection, invasion,
and sepsis. About 40 million chronic wounds are treated globally
annually. Those are wounds that get stuck in the inflammatory stage
of wound healing and do not heal. Chronic wounds are the source of
severe emotional and physical stress for patients and create a
significant financial burden, both on patients and the whole
healthcare system. In the chronic wound the balance between
production and degradation of proteins is lost and degradation
plays too large a role.
Chronic wounds present an enormous physical, social and economic
burden worldwide and their incidence is on the rise with an aging
population. It has been estimated that chronic wounds affect 120
per 100,000 people aged between 45 and 65 years and increases to
800 per 100,000 people aged over 75 year. Chronic wounds result
from a number of different causes among them diabetes, pressure,
atrial and venous insufficiency, vasculitis and burns. Additional
complications, including infections, necrosis, tissue hypoxia, and
exudates represent further challenges in dealing with a chronic
wound. Poor nutrition, obesity, excessive alcohol consumption and
smoking can then add an additional layer of complications to an
already serious condition.
Normal wound healing progresses through three stages. The first is
Inflammation that lasts 2 to 4 days from the time of injury. Upon
injury hemostasis causes vascular constriction, and thrombus
formation. Platelets in the wound release factors that recruit
neutrophils and monocytes (macrophages), which in turn attract
lymphocytes and fibroblasts to the site of injury. The
proliferation stage overlaps the inflammatory stage, starts at
about day 3 and lasts for several days. It is characterized by
angiogenesis, collagen formation and epithelialization mediated by
fibroblasts, and is complete when balance is achieved in collagen
formation and its continuous breakdown by matrix metallo-proteases
(MMPs). The Remodeling stage is the third and last stage and can
extend over a year or more. Collagen remodeling continues,
fibroblasts differentiate into myofibroblasts, vascularity
decreases and tissue strength increases.
Bedsores, more properly known as pressure ulcers or decubitus
ulcers, are lesions caused by many factors such as: unrelieved
pressure; friction; humidity; shearing forces; temperature; age;
continence and medication; to any part of the body, especially
portions over bony or cartilaginous areas such as sacrum, elbows,
knees, and ankles Although easily prevented and completely
treatable if found early, bedsores are often fatal--even under the
auspices of medical care--and are one of the leading iatrogenic
causes of death reported in developed countries, second only to
adverse drug reactions.
Results from a small trial utilizing a modified version of the burn
cream are presented herein for the treatment of chronic wounds.
Cracked Heels
Cracked heels are a common foot problem and are often referred to
as heel fissures. Cracked heels are commonly caused by dry skin
(xerosis), and made more complicated if the skin around the rim of
the heel is thick (callus). For most people this is a nuisance and
a cosmetic problem but when the fissures or cracks are deep, they
are painful to stand on and the skin can bleed--in severe cases
this can become infected.
The skin is normally dry and may have a thick callus that appears
as a yellow or dark brown discolored area of skin, especially along
the inside border of the heel. Cracks in the skin are usually
obvious.
If the cracks are severe enough, there will be pain upon weight
bearing that is not there when weight is off the heel. The edges or
rim around the heel will generally have a thicker area of skin
(callus). Wearing open or thin-soled shoes usually make the
symptoms worse.
Some people tend to have a naturally dry skin that predisposes them
to the cracks. The thickened dry skin (callus) around the heel that
is more likely to crack is often due to mechanical factors that
increase pressures in that area.
Other factors that can be involved in the cause of cracked heels
include: prolonged standing (at work or home, especially on hard
floors) being overweight (this increases the pressure on the normal
fat pad under the heel, causing it to expand sideways--if the skin
is not supple and flexible, the pressures to `crack` are high) open
back on the shoes (this allows the fat under the heel to expand
sideways and increases the pressure to `crack`) some medical
conditions predispose to a drying skin (e.g. autonomic neuropathy
in those with diabetes leads to less sweating; an underactive
thyroid lowers the body's metabolic rate and there is a reduction
in sweating, leading to a dryness of the skin) skin conditions
(e.g. psoriasis and eczema).
Results from a small trial utilizing a modified version of the burn
cream are presented herein for the treatment of cracked heels.
SUMMARY OF THE INVENTION
Background
Both the nature of the wound and microorganism-specific factors
influence the rate of microbial proliferation in and penetration of
the wound tissue. The wound is rich in coagulated protein and well
hydrated by the trans-eschar movement of fluid and serum, creates
an excellent microbial culture medium. The eschar is avascular
owing to thrombosis of nutrient vessels, limiting both the delivery
of systemically administered antibiotics and the migration of
phagocytic cells into the burned tissue. Bacterial proliferation in
the wound also can be enhanced by such factors as wound maceration,
pressure necrosis, and wound desiccation with neo-eschar formation.
In addition, secondary impairment of blood flow to the wound could
further predispose the patient to invasive infection by curtailing
the delivery of oxygen, nutrients, and phagocytic cells to the
viable sub-eschar tissue.
The character of the microbial flora of the burn wound changes with
time and Gram-negative organisms replace Gram-positive organisms
that predominate in the early post wound period by the second week.
Without the application of topical antimicrobial agents, the
density of bacteria progressively increases, and the microorganisms
penetrate the eschar by migration along sweat glands and hair
follicles until they reach the eschar/nonviable tissue interface.
If the density and invasiveness of the microorganisms exceed the
host's defense capacity, proliferating organisms in the sub-eschar
space can invade the underlining viable tissue, leading to invasive
burn wound infection and even systemic spread to remote tissues and
organs. Bacterial invasion is uncommon unless the number of
microorganisms exceeds 10.sup.5/grams of biopsy tissue. Effective
topical antimicrobial chemotherapy limits intra-eschar bacterial
proliferation and the attendant risk of invasive infection.
Over the past 20 years, significant changes in the microbial
ecology of the burn wound have been noted. The recovery of
Pseudomonas and other gram-negative bacteria, which were once the
most common organisms causing burn wound infection, has markedly
declined with improvements in the isolation of patients. Patients
who have received broad-spectrum antibiotics for perioperative
coverage or treatment of septic complications and whose wounds
remain open for many days owing to the extent of the burn are at
increased risk of burn wound colonization and infection by yeasts,
fungi, and multiple antibiotic-resistant bacteria. The true fungi
have replaced bacteria as the most common microbes causing burn
wound infection in recent years. Pseudomonas aeruginosa,
Staphylococcus aureus and Aspergillus species are the commonest
organisms associated with burn wound infection.
Mafenide acetate, 1% SSD and silver nitrate are the three most
commonly employed topical antimicrobial agents for burn wound care.
Each agent has specific limitations and advantages.
1% SSD burn cream is most effective when applied to burns soon
after injury to minimize bacterial proliferation on the wound's
surface. It has limited solubility in water and, therefore, limited
ability to penetrate into the eschar. With continual use,
resistance to the sulfonamide component of 1% SSD is common,
particularly in certain strains of Pseudomonas and many
Enterobacter species. Mafenide acetate diffuses freely into the
eschar owing to its high degree of water solubility. It is the
preferred agent if the patient has heavily contaminated burn wounds
or has had burn wound care delayed by several days.
Hypersensitivity reactions occur in 7% of patients. This agent also
inhibits carbonic anhydrase, and a diuresis of bicarbonate often is
observed after its use. The resultant metabolic acidosis could
accentuate post-burn hyperventilation, and significant acidemia
could develop if compensatory hyperventilation is impaired. A 0.5%
silver nitrate solution has a broad spectrum of antibacterial
activity imparted by the silver ion. This agent does not penetrate
the eschar because the silver ions are rapidly precipitated on
contact with any protein or cationic material.
It is clear that the topical agents are crucial in the ultimate
eradication of the burn and infected wound pathogens since it is
extremely difficult to administer the intravenous antibiotics to
non-perfused tissue such as burned skin. The poorly vascularized,
wounded skin is, therefore, the portal of entry and the ongoing
nidus of infection for burn victims. The ideal topical agent should
be highly active against common and multi-resistant pathogens, such
as methicillin resistant Staphylococcus aureus, vancomycin
resistant Enterococcus faecium/faecalis, and extended spectrum
.beta.-lactamase producing Gram- negative organisms, while having a
neutral or even beneficial effect on the wound healing process.
Antimicrobial peptides represent a relatively new discovery in the
immune system path-way. These small peptides are inducible elements
of the immune system that serve as nonspecific effector molecules
to eradicate infection caused by bacteria, yeast, and viruses,
protecting host epithelial surfaces such as the tracheal mucous
membrane and genitourinary tract. In mammals, several of these
compounds are known to be present in high concentrations in
neutrophilic granules and phagocyte vacuoles. These peptides differ
significantly in their structure between species but, in common,
appear to create amphipathic helical or beta-pleated structures.
The mechanism of action is different from currently utilized
antibiotics and appears to be based on their ability to insert into
membranes, from channels or "pores", and destroy the cell by
changing membrane conductance and altering intracellular function.
Based upon the principles discovered in naturally occurring
peptides, recent designs of synthetically engineered antimicrobial
peptides have demonstrated increased potency and
efficacy/tolerability, enhanced specificity, and reduced toxicity
in comparison. These peptides termed as designed antimicrobial
peptides (dAMP), are resistant to such effects of high solute
levels and demonstrate even greater antibacterial activity.
One such peptide, XYLENTRA.RTM., has showed significant promise
from significant in vitro studies against a large number of
pathogens through to extensive animal studies and is very solute
resistant. These types of antimicrobial peptides show enormous
promise in treating patients with chronic wounds or burn wound
sepsis. The impact of this would improve patient survival or
quality of life and reduce costs to the patient, their family,
hospital and society.
The peptide XYLENTRA.RTM. showed significant antibacterial activity
on test organisms Staphylococcus aureus MTCC 96and Pseudomonas
aeroginosa MTCC 741. The test compound showed 100% killing of
Staphylococcus aureus on exposure to 1 .mu.M (4.3 .mu.g/ml) and 5
.mu.M (21.5 .mu.g/ml) concentrations for 1 hr at pH 7.2, and at pH
8.4 an exposure of 4 hrs was required to get 100% killing. Whereas,
100% killing of Pseudomonas aeroginosa was observed on exposure to
the test compound for 1 hr at pH 8.4 and an exposure of 4 hrs was
required for 100% killing at pH 7.2.
The microbiological studies with XYLENTRA.RTM. in vivo using a rat
burn wound model were conducted. The observations on the bacterial
growth in eschar and sub-eschar muscles on post burn day one, two
or three in peptide treated and control treated groups were made. A
substantial decrease in the microbial population level was observed
in animals treated with peptide.
Subacute toxicity studies of XYLENTRA.RTM. in rats and rabbits
demonstrated that it was safe. No abnormalities in physical,
physiological, biochemical and histo-pathological parameters were
observed on application of the peptide. No mortality was seen in
animals from any group. There is evidence (dermal histopathology
findings) to show that XYLENTRA.RTM. has stimulatory action on
tissue growth (increased collagen content in granulation tissue and
re-epithelialization) thus promoting improved wound healing
(unpublished observations).
The results of a Phase-I clinical trial (n=24) on healthy human
patients revealed that XYLENTRA.RTM. cream administered topically
twice a day was safe. There was an absence of any symptoms or signs
of toxicity at the evaluation site and considered a measure of
primary efficacy/tolerability was established in this study.
XYLENTRA.RTM. was safe and adverse events were found to be minimal
in tire Phase-I Study. Mild redness and itching was seen in 2/24
volunteers. Treatment Groups (2% and 4%) were similar in
efficacy/tolerability and safety parameters studied.
Pharmacokinetic data was analyzed by HPLC at different time
intervals and suggested no systemic absorption of the drug.
It was demonstrated in a phase II study (n=120) with the
XYLENTRA.RTM. Peptide Treatment Groups (0.02% & 0.05%) dial the
incidence rate of wound healing was better in terms of time to
complete wound healing and achievement of a superior overall wound
evaluation score over the Placebo Group. Scar formation was also
significantly lower compared to that in Placebo Group, indicating
that treatment with XYLENTRA.RTM. enabled more complete healing
with less morbidity. It is safe and highly effective in promoting
burn wound healing for patients with partial thickness burns that
are less than or equal to 20% without any side effects. None of the
XYLENTRA.RTM. treated volunteers developed any adverse reaction.
Pharmacokinetic data suggested the absence of systemic
absorption.
Description of XYLENTRA.RTM.
Description of Xylentra
The proprietary cream mixture proven to be efficacious in treating
burn, chronic and cracked heel wounds is composed of a sufficient
amount of the peptide:
FAKKFAKKFAKFAKKFAKFAFAF (SEQ ID NO:1) and a cream with the
following composition found in Table 1.
Results of Phase III Burn Trial
Study Objective
To compare safety and efficacy of 1% SSD with XYLENTRA.RTM. in
patients with partial thickness burns in India.
In India about 60,000 people suffer from burns annually, more than
50,000 are treated in hospitals and about 10,000 succumb to thermal
injury. Exact figures are likely to be even higher, considering the
poverty, illiteracy, poor standards of safety at home and industry.
Thus the burn `disease` is endemic in India. House and structuale
fires are responsible for >70% of the yearly 3,785 burn-related
deaths, 75% of which result from smoke inhalation or asphyxiation
and 25% are due to burns. Injuries due to contact with flame or
ignition of clothing are the most common cause of burn in adults
whereas scald burns are most common in children. The majority of
patients sustain burns of such limited severity and extent (>80%
of burns involve <20% of the body surface) that they can be
treated on an outpatient basis. Approximately 33% of patients who
require in-hospital care have a major burn injury as defined by the
American Burn Association on the basis of burn size, causative
agent, and associated injuries and should be treated in a tertiary
care burn center.
Study Population
Patients of either gender with partial thickness burns referred to
a tertiary referral center Number of Subjects Enrolled: 160
Methodology
1. Study Design a. Multi-center, double-blind, randomized parallel
design study in 200 patients of partial thickness burns 2. Study
Period a. 12 months 3. Study Procedure a. Participants satisfying
the inclusion criteria were hospitalized for the study duration and
were randomized in a 1:1 ratio to receive either SSD 1% or
XYLENTRA.RTM.. Randomization was done specific for each center.
Allocation concealment was maintained. The drugs were topically
administered once daily for 4 weeks or until complete wound
healing, whichever was earlier. The patients were discharged only
after complete healing of wound and recovery from other secondary
effects of burns. A follow up was done on the 3.sup.rd month to
record the frequency of scars.sup.10, keloids or contracture
formation. b. Key Criteria for Inclusion/Exclusion: i. Inclusion:
1. Either sex 2. Age 18-60 years 3. Those diagnosed with partial
thickness thermal burns as per clinically 4. Total surface area of
the burn 10-20% as per Wallace rule of nine 5. Willing to give
written informed consent. 6. Females of child-bearing potential
with a negative urine pregnancy test on Day 1 7. Weight range
within 20% of the ideal body weight as per standard tables and
Indian criteria ii. Exclusion: 1. History of intercurrent illnesses
2. History of drug addiction 3. History of chronic GI, renal,
hepatic, respiratory, infectious, or History of allergy or
hypersensitivity to investigational drugs 4. Chronic smokers and/or
history 5. Patients with pulmonary burn 6. Patients with chemical
or electrical burns 7. Patients taking any antibiotics
Investigational Product
XYLENTRA.RTM.
Dose
4 gms/1% burn
Mode of Administration
Topical
Duration of Treatment
For 4 weeks or till the day of complete wound healing whichever was
earlier.
Criteria for Evaluation
Primary variable 1. Proportion of patients having complete
closure/healing of the wounds during 28 days a. Time points to
measure endpoint: 1, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26
and 28.+-.1 days
Primary variable 2. Proportion of patient with controlled secondary
infection during 28 days a. Time points to measure endpoint: 1, 4,
8, 12, 16, 20, 24 and 28.+-.1 days
Secondary variables 1. Extent of non-viable tissue by clinical
evaluation % of wound covered with non-viable tissue (clinically)
76-100% 51-75% 26-50% 1-25% No Necrotic Tissue 2. Degree of
granulation by visual Score % of wound filled with granulation
tissue (clinically) No Granulation Scanty Granulation Healthy
Granulation 3. Wound Evaluation Done on Four Parameters
(clinically): Erythema (redness of the skin caused by dilatation
and congestion of the capillaries, often a sign of inflammation or
infection) Edema (excessive accumulation of serous fluid in tissue
spaces) Purulence (the state or condition of containing or
secreting pus) Necrotic Tissue (dead, devitalized tissue)
Each of these parameters is measured on a scale of 0-3 as
follows:
0=Absent; 1=Mild; 2=Moderate; 3=Severe. 4. Complete closure/healing
of the wound (clinically). [Time Frame (in days): Admission to burn
unit to 100% wound healing] a. Time points to measure secondary
endpoint: 1, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26 and
28.+-.1 days. Safety
Safety was measured by pretreatment and post treatment biochemical
investigations (Hematological variables) and physical examination.
Subjects were thoroughly monitored for adverse effects.
Conclusions
One hundred and sixty patients completed the study. The objective
was to compare the safety and efficacy of XYLENTRA.RTM. with Silver
Sulfadiazine in patients with partial thickness burns. The patients
were topically administered with either XYLENTRA.RTM. or Silver
Sulfadiazine cream based on allocation concealment once daily for 4
weeks or until complete wound healing whichever is earlier.
The study met its primary endpoints. The proportion of patients
with complete wound closure, was statistically significant between
the XYLENTRA.RTM. and Silver Sulfadiazine group. The patients with
complete wound closure were 75 (94%) (N=80) and 65 (81%) (N=80) in
the XYLENTRA.RTM. and Silver Sulfadiazine groups, respectively in
the four week time period. Moreover, XYLENTRA.RTM. demonstrated
accelerated healing rates when compared to Silver Sulfadiazine. The
time taken for complete wound closure was found to be less in
Xylentra group compared to Silver Sulfadiazine group as more number
of patients had complete wound closure at various time points in
the XYLENTRA.RTM. group when comparison to the Silver Sulfadiazine
group. Cumulative wound healing was found to be better in
XYLENTRA.RTM. group when compared to Silver Sulfadiazine group.
Cumulative wound healing was 85.42% XYLENTRA.RTM. group and 78.71%
in Silver Sulfadiazine.
Burn wounds are a richer source of infection than surgical wounds,
primarily because of the larger area involved and longer duration
of patient stay in the hospital, in this study, clinical and
statistically significant differences were found in the proportion
of patients with controlled secondary infections between the
groups. XYLENTRA.RTM. showed increased efficacy in controlling the
infection rate as evident front 41.7% of patients with controlled
secondary infection in the XYLENTRA.RTM. group when compared to 25%
of patients with controlled secondary infection in Silver
Sulfadiazine group. Additionally, antibiotic usage was lower by
patients in the XYLENTRA.RTM. group when compared to the Silver
Sulfadiazine group.
Most commonly encountered and clinically significant impediments to
wound healing are the presence of non-viable tissue and
granulation. XYLENTRA.RTM. proved to be efficacious in controlling
both non-viable tissue and granulation throughout the study period.
Both the evaluation of mean score of non-viable tissue and patient
wise evaluation confirmed that XYLENTRA.RTM. remarkably reduced
non-viable tissue and granulation in comparison to Silver
Sulfadiazine. On study termination day, no non-viable tissue was
found in 78 (97.50%) and 71 patients (88.75%) in XYLENTRA.RTM. and
Silver Sulfadiazine groups, respectively. It was clinically
observed that non-viable tissue became necrotic tissue in the
Silver Sulfadiazine treated patients. However non-viable tissue
appeared during the initial visits in XYLENTRA.RTM. treated
patients but no necrotic tissue was observed during the study
period. Similarly, at the end of study termination day, the number
of patients observed with no granulation in XYLENTRA.RTM. group was
75 (93.75%) and 63 (78.75%) in the Silver Sulfadiazine group.
XYLENTRA.RTM. also proved to be potent in wound evaluation based on
clinical parameters. It was effective in controlling edema,
erythema and purulence as evident from the results of mean score
analysis and patient wise analysis. Patients with no edema, no
erythema and no purulence were found to be less in number in
XYLENTRA.RTM. group when compared to Silver Sulfadiazine group. On
study termination day, no erythema was found in 78 (97.50%) and 74
patients (92.50%) in XYLENTRA.RTM. and Silver Sulfadiazine groups
respectively. No edema was found in 79 (98.75%) and 74 (92.50%) in
XYLENTRA.RTM. and Silver Sulfadiazine groups, respectively. No
purulence was found in 78 (97.50%) and 74 (92.50%) patients in
XYLENTRA.RTM. and Silver Sulfadiazine groups, respectively. In
addition, the mean scores of erythema, edema and purulence were
found to be considerably lower in XYLENTRA.RTM. group in comparison
to Silver Sulfadiazine group. In addition to these primary efficacy
and secondary efficacy endpoints, other variables that demonstrate
the potency of the drug such as drug's ability to reduce scar
(pigmentation and thickness), itching and breaking were evaluated.
Scar maturation and normal skin formation always will be depending
on the quality of wound healing. Patients of post-burn
contractures, scars defects and disfigurements constitute almost
half of the workload of many general plastic surgeons; especially
this will directly increase the cost to patient for surgical
procedures. Hence choosing the quality healing medicine is very
important step in burn wound management. The clinical observations
showed that most of the XYLENTRA.RTM. treated patients' wound area
returned to their normal skin color without any scar or contracture
formation. However, most of the patients treated with Silver
Sulfadiazine had dark pigmentation with hypertrophic scars with
contractures. Hyper pigmentation and hypo pigmentation was
significantly less in XYLENTRA.RTM. group (13% and 16%) when
compared to Silver Sulfadiazine group (25% and 21%). The area with
paper thin and hypertrophic scar was more than twice in Silver
Sulfadiazine group (6% and 25%) when compared to XYLENTRA.RTM.
group (2% and 12%). Itching was found significantly greater in
treated patients (51%) in Silver Sulfadiazine group in comparison
to XYLENTRA.RTM. group (14%). In addition, 18% of treated patients
in Silver Sulfadiazine group had breaking of skin in comparison to
3% of treated patients in XYLENTRA.RTM.. These results demonstrate
the fact that XYLENTRA.RTM. has the ability to heal the wound
effectively and controlling the development of scars, pigmentation,
itching and breaking.
The treatment emergent adverse events (TEAEs) observed were mostly
skin related disorders. All the adverse events were found to be
mild in nature. No serious adverse events and no deaths were
reported in the study. The adverse events frequently experienced by
patients in the study were swelling, irritation, itching, redness
and pain. All these adverse events were observed in high percentage
of patients and were present for longer duration in Silver
Sulfadiazine group when compared to XYLENTRA.RTM. group.
Burn Wounds
A summary of the statistical measurements of the test variables is
listed in Table 2.
Photographic comparison of both treatments can be found in FIGS. 1A
and B.
Diabetic Wound Experiments
Patients were treated with the XYLENTRA.RTM. cream once per day for
the indicated times listed on FIG. 2.
Other Types of Chronic Wounds:
Cracked Feet Experiments
Patients were treated with the XYLENTRA.RTM. cream once per day for
the indicated times listed on FIG. 3.
BRIEF DESCRIPTION OF FIGURES
FIG. 1A and FIG. 1B--Photographic comparison of burn treatments can
be found in both FIG. 1A and FIG. 1B.
FIG. 2. Patients were treated with the XYLENTRA.RTM. cream once per
day for the indicated times listed in the Figure.
FIG. 3. Patients were treated with the XYLENTRA.RTM. cream once per
day for the indicated times listed in the Figure.
TABLE-US-00001 TABLE 1 Composition of Cream 1 Cetomacrogol-1000
2-5% 2 Stearyl Alcohol 8-15% 3 Liquid Paraffin 3-6% 4 White
Petrolium Jelly 15-20% 5 Propylene Glycol 6-10% 6 Peptide 0.05-2.0%
7 Sodium Methyl Paraben 0.1-0.2% 8 Sodium Propyl Paraben 0.05-0.1%
9 Sodium Phosphate 0.1-0.3% 10 Sodium Acid Phosphate 0.01-0.03% 11
EDTA Disodium 0.01-0.03% 12 Citric Acid 0.3-0.8% 13 Purified Water
50-65%
TABLE-US-00002 TABLE 2 Summary of Statistical Measurements of Test
Variables p-value Significant Primary Variables Variable 1 %
Patients achieving complete wound closure/healing 0.005 YES
Variable 2 % Patients with controlled secondary infections 0.017
YES Secondary Variables Variable 1 % of wound covered with
non-viable tissue <0.001 YES Variable 2 Degree of granulation
0.026 YES Variable 3 Erythema 0.310 NO Edema 0.204 NO Purulence
0.019 YES Necrotic Tissue 0.035 YES Variable 4 Time to achieve
complete closure/wound healing <0.0001 YES Additional Variables
Scarring % Normal Skin <0.001 YES % Hypertrophic Scar 0.005 YES
% Paper Thin Scar 0.027 YES % Raw Area 0.136 NO % Itching 0.001 YES
% Breakdown of Skin 0.006 YES % Normal Pigmentation <0.001 YES %
Hyper Pigmented Scar 0.004 YES % Hypo Pigmented Scar 0.066 NO %
Mottled Scar 0.470 NO
SEQUENCE LISTINGS
1
1123PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 1Phe Ala Lys Lys Phe Ala Lys Lys Phe Ala Lys Phe
Ala Lys Lys Phe1 5 10 15Ala Lys Phe Ala Phe Ala Phe 20
* * * * *